United States Patent [19]
`Junggren et al.
`
`[ ll]
`
`4,255,431
`
`[45]
`Mar. 10, 1981
`
`[54] GASTRIC ACID SECRETION INHIBITING
`OTHER PUBLICATIONS
`SUBSTITUTED
`
`Berntsson et al., Chern. Abst., 1976, vol. 85, No.
`2-(2-BENZIMIDAZOLYL)·PYRIDINES,
`l49 l39q.
`PHARMACEUTICAL PREPARATIONS
`Hideg et al., Chern. Abst., 1971, vol. 75, No. 98570g.
`CONTAINING SAME, AND METHOD FOR
`INHIBITING GASTRIC ACID SECRETION
`Primary Examiner-Henry R. Jiles
`A. Schwartz
`
`Assistant Examiner-Richard
`
`Agent, or Firm-Brumbaugh, Graves,
`Attorney,
`Donohue & Raymond
`[57]
`ABSTRACT
`
`
`The present invention relates to novel compounds of
`the formula
`
`Ulf K. Junggren, MOlnlycke;
`[75] Inventors:
`Sven E.
`
`Sjastrand, Kungsbacka, both of
`Sweden
`
`
`[73] Assignee: Aktiebolaget Hassle, MOindal,
`Swe den
`[21] Appl. No.: 27,277
`
`[22] Filed: Apr. 5, 1979
`[30) Foreign Application
`
`Priority Data
`Apr. 14, 1978 [SE] Sweden ................................ 7804231
`
`[51] Int. CJ.J ..................... A61K 31/44; C07D 401/12
`[52] u.s. Cl • .................................... 424/l63;
`546/271;
`wherein Rl and R2 are the same or different and are
`
`
`546/301; 548/329
`
`
`each hydrogen, alkyl, halogen, carbomethoxy, carbe­
`
`[58] Field of Search ......................... 546/271; 424/263
`
`
`
`thoxy, alkoxy, or alkanoyl, R6 is hydrogen, methyl or
`
`ethyl, R3, R4 and R5 are the same or different and are
`References Cited
`
`
`each hydrogen, methyl, methoxy, ethoxy, methoxye­
`U.S. PATENT DO CUMENTS
`
`thoxy or ethoxyethoxy whereby R3, R4 and R5 are not
`and whereby when two of R3, R4 and R5
`all hydrogen,
`8/1977 Berntsson
`4,045,563
`et al .................... 546/271
`are hydrogen the third of R3, R4 and R5 is not methyl.
`8/1977 Berntsson
`4,045,564
`et al. ................... 546/271
`
`
`
`The compounds are potent gastric acid secretion inhibi­
`1/1980 Krasso
`4,182,766
`et al. .................... 546/27l X
`tors.
`FOREIGN PATENT DOCUMENTS
`
`1804450 5/1970 Fed. Rep. of Germany ........... 546/271
`
`29 Claims, No Drawings
`
`[56)
`
`

`
`1
`
`4,255,431
`
`Halogen Rl and R2 are chloro, bromo, fluoro, or
`
`2
`wherein R 1 and R 2 are same or different and are each
`
`
`
`
`selected from the group consisting of hydrogen, alkyl,
`GASTRIC ACID SECRETION INHIBITING
`
`
`
`
`halogen, carbomethoxy, carbethoxy, alkoxy, and alkan­
`SUBSTITUTED
`
`
`oyl, R 6 is selected from the group consisting of hydro-
`2-(2-BENZIMIDAZOLYL)-PYRIDINES,
`5 gen, methyl, and ethyl, and R3, and R5 are the same or
`
`PHARMACEUTICAL PREPARATIONS
`
`
`different and are each selected from the group consist­
`CONTAINING SAME, AND METHOD FOR
`
`
`ing of hydrogen, methyl, methoxy, ethoxy, methoxye­
`
`INHIBITING GASTRIC ACID SECRETION
`
`thoxy and ethoxyethoxy and R4 is methoxy, ethoxy,
`
`
`methoxyethoxy or ethoxyethoxy whereby R3, R4, and
`The present invention relates to new compounds
`
`
`acid se-10
`
`R5 are not all hydrogen, and whereby when two of R3,
`
`
`
`having valuable properties in affecting gastric
`
`R4, and R5 are hydrogen, the third of R3, R4 and R5 is
`
`
`cretion in mammals, including man, as well as the pro­
`not methyl.
`
`
`cess for their preparation, method of affecting gastric
`Alkyl Rl and R2 of formula III are suitably alkyl
`
`
`
`
`acid secretion and pharmaceutical preparations contain­
`
`having up to 7 carbon atoms, preferably up to 4 carbon
`ing said novel compounds.
`The object of the present invention is to obtain com-15
`
`atoms .. Thus, alkyl R may be methyl, ethyl, n-propyl,
`
`
`
`isopropyl, n-butyl or isobutyl.
`
`
`pounds which affect gastric acid secretion, and which
`
`
`
`
`
`inhibit exogenously or endogenously stimulated gastric
`iodo.
`
`acid secretion. These compounds can be used in the
`Alkoxy Rl and R2 are suitably alkoxy groups having
`
`
`treatment of peptic ulcer disease.
`up to 3 carbon atoms,
`It is previously known that compounds of the formu-20
`
`up to 5 carbon atoms, preferably
`
`
`
`such as methoxy, ethoxy, n-propoxy, or isopropoxy.
`las I and II
`
`Alkanoyl Rl and R2 have preferably up to 4 carbon
`
`
`
`
`atoms and are e.g. formyl, acetyl, or propionyl, prefera­
`(I)
`bly acetyl.
`25
`A preferred group of compounds of the general for­
`
`
`mula III are those wherein Rl and R2 are the same or
`
`
`different and are each selected from the group consist­
`
`
`ing of hydrogen, alkyl, carbomethoxy, alkoxy, and al­
`
`kanoyl, whereby Rl and R2 are not both hydrogen,
`R6
`30
`
`is hydrogen, and R3, R4, and R5 are the same or differ­
`(II)
`
`
`ent and are each selected from the group consisting of
`
`hydrogen, methyl, methoxy, and ethoxy, whereby R3,
`
`R4, and R5 are not all hydrogen, and whereby when two
`of R3, R4, and R5 are hydrogen the third of R3, R4, and
`35 R5 is not methyl.
`A second preferred group of compounds of the gen­
`
`
`eral formula III are those wherein R 1 and R 2 are the
`
`
`same or different and are each selected from the group
`wherein Rl and R2 are each selected from the group
`
`
`
`
`consisting of hydrogen, alkyl, halogen, carbomethoxy,
`40
`
`
`
`
`consisting of hydrogen, alkyl, halogen, cyano, carboxyl,
`
`
`
`carbethoxy, alkoxy, and alkanoyl, R6 is selected from
`
`
`
`carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbam­
`
`
`the group consisting of hydrogen, methyl, and ethyl,
`oyl, carbamoyloxy, hydroxy, alkoxy, · hydroxyalkyl,
`
`
`
`
`R3 is methyl, R4 is methoxy, and R5 is methyl.
`
`
`trifluoromethyl and acyl in any position, R3 is selected
`
`A third preferred group of compounds of the general
`
`
`from the group consisting of hydrogen, alkyl, acyl,
`formula III are those wherein R I and R2 are the same or
`
`
`
`carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcar-
`45
`
`
`different and are each selected from the group consist­
`
`bamoyl, alkylcarbonylmethyl, alkoxylcarbonylmethyl,
`
`
`
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe-
`and alkylsulphonyl, and R4 is selected from the group
`
`
`
`
`thoxy, alkoxy and alkanoyl, R6 is selected from the
`
`
`
`consisting of straight and branched alkylene groups
`
`
`group consisting of hydrogen, methyl and ethyl, and R3
`having 1 to 4 carbon atoms, whereby at most one meth­
`
`is hydrogen, R4 is methoxy and R5 is methyl or R3 is
`
`
`ylene group is present between S and the pyridyl group, 50
`
`methyl, R4 is methoxy and R5 is hydrogen.
`
`and whereby the pyridyl group may be further substi­
`
`A fourth preferred group of compounds of the gen­
`
`tuted with alkyl or halogen, possess an inhibiting effect
`
`
`eral formula III are those wherein R 1 and R 2 are the
`
`on gastric acid secretion.
`
`
`same or different and are each selected from the group
`
`
`It has now, however, surprisingly been found that the
`
`
`
`consisting of hydrogen, alkyl, halogen, carbomethoxy,
`55
`
`compounds defined below possess a still greater inhibit-
`
`
`
`carbethoxy, alkoxy, and alkanoyl, R6 is selected from
`ing effect than those given above.
`
`
`the group consisting of hydrogen, methyl and ethyl,
`R3
`Compounds of the invention are those of the general
`
`and R5 are hydrogen and R4 is methoxy.
`formula III
`
`A fifth preferred group of compounds of the general
`formula III are those wherein R I and R 2 are the same or
`(III) 60
`
`
`different and are each selected from the group consist­
`
`
`
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe­
`
`
`thoxy, alkoxy, and alkanoyl, R 6 is selected from the
`
`
`group consisting of hydrogen, methyl and ethyl, and R3
`and R5 are methyl and R4 is hydrogen.
`65
`
`
`A sixth preferred group of compounds of the general
`formula III are those wherein R 1 and R 2 are the same or
`
`
`different and are each selected from the group consist­
`
`
`
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe-
`
`

`
`4,255,431
`
`4
`
`5 ,Re2· ...
`:; .N
`R' · . . . . .
`. � . N I 'H
`
`(VII)
`
`>-z'
`
` ,
`
`.•
`
`3
`thoxy, alkoxy, and alkanoyl, R6 is selected from the
`
`
`
`group consisting of hydrogen, methyl and ethyl, R 3 and
`
`
`R5 are hydrogen and R4 is ethoxy, methoxyethoxy or
`ethoxyethoxy.
`A seventh preferred group of compounds of the gen­
`
`
`eral formula III are those wherein Rl and R2 are the
`
`
`same or different and are each selected from the group
`
`
`
`consisting of hydrogen, alkyl, halogen, carbomethoxy,
`10 wherein Rl, and R2 have the same meanings
`as given
`
`
`alkoxy, and alkanoyl, R6 is selected from the group
`
`
`above and z1 is SH or a reactive esterified hydroxy
`
`consisting of hydrogen, methyl, and ethyl, R3, R4, and
`
`group, with a compound of the formula VIII
`R5 are all methyl.
`
`Other groups of compounds which may be used are:
`methyl, 15 Compounds in which R 1 is hydrogen, chloro,
`
`
`
`
`
`ethyl, methoxy, acetyl, carboethoxy or carbomethoxy;
`
`R2 is hydrogen or methyl; R6 is hydrogen, methyl or
`
`ethyl; R3 and R5 are methyl; and R4 is methoxy. Com­
`pounds in which R I is hydrogen,
`20
`
`chloro, methyl, ethyl,
`
`
`
`methoxy, acetyl, carboethoxy or carbomethyl; R2 is
`wherein R6, R3, R4, and R5 have the same meanings as
`
`
`hydrogen, methyl or ethyl; R4 is methoxy; and R3 is
`
`
`
`given above, and z2 is a reactive esterified hydroxy
`methyl and R5 is hydrogen or R3 is hydrogen
`and R5 is
`
`
`group or SH, to the formation of an intermediate of
`methyl.
`
`
`formula IV above, which then is oxidiz.ed to give a
`25
`compound of formula III;
`Compounds of formula III above may be prepared
`
`(d) reacting a compound of the formula IX
`
`
`according to the following methods:
`
`(a) oxidizing a compound of formula IV
`
`(VIII)
`
`30
`(IV)
`
`R-02 -NH2
`R' NH2
`
`(IX)
`
`35
`wherein Rl and R2 have the same meanings as given
`
`
`above with a compound of the formula X
`
`wherein Rl, R2, R6, R3, R4, and R5 have the meanings 40
`
`given, to the formation of a compound of formula III.
`
`(b) reacting a compound of the formula V
`
`(X)
`
`(V) 45
`wherein R6, R3, R4, and R5 have the same meanings
`as
`
`
`given above, to the ·formation of an intermediate of
`
`formula IV above, which then is oxidized to give a
`compound of formula III, which compound may be
`50 converted
`
`
`
`to its therapeutically acceptable salts, if so
`desired.
`above, Z, z1, and z2 may be a reac-
`In the reactions
`wherein Rl, R2, and R6have the meanings given above
`
`
`tive, esterified hydroxy group which is a hydroxy group
`
`
`
`
`esterified with strong, inorganic or organic acid, prefer­
`
`
`and M is a metal selected from the group consisting of
`K, Na and Li, with a compound of formula VI. 55
`
`
`ably a hydrohalogen acid, such as hydrochloric acid,
`
`
`
`
`hydrobromic acid, or hydroiodic acid, also sulfuric acid
`
`or a strong organic sulfonic acid as a strong aromatic
`(VII)
`
`acid, e.g. benzenesulfonic acid, 4-bromobenzenesulfonic
`
`acid or 4-toluenesulfonic acid.
`60
`
`The oxidation of the sulfur atom in the chains above
`
`to sulfinyl (S---+0) takes place in the presence of an
`
`
`
`oxidizing agent selected from the group consisting of
`
`
`nitric acid, hydrogen peroxide, peracids, peresters,
`
`
`ozone, dinitrogentetraoxide, iodosobenzene, N-halosuc­
`wherein R3, R4, and R5 have the same meanings as 65
`
`
`cinimide, 1-chlorobenzotriazole, t-butylhypochlorite,
`given above, Z is a reactive
`
`esterified hydroxy group, to
`
`diazobicyclo-[2,2,2,]-octane bromine complex, sodium
`
`the formation of a compound of formula III;
`
`
`metaperiodate, selenium dioxide, manganese dioxide,
`
`
`(c) reacting a compound of the formula VII
`
`
`
`chromic acid, cericammonium nitrate, bromine, chlo-
`
`

`
`4,255,431
`
`5
`6
`
`
`
`
`
`rine, and sulfuryl chloride. The oxidation usually takes amount of active compound is between 0.1 to 95% by
`
`
`agent is present place in a solvent wherein the oxidizing
`
`weight of the preparation, between 0.5 to 20% by
`
`in some excess in relation to the product to be oxidized.
`
`
`weight in preparations for injection and between 2 and
`
`
`
`Depending on the process conditions and the starting
`
`50% by weight in preparations for oral administration.
`either as the free 5
`the end product is obtained
`materials,
`
`
`In the preparation of pharmaceutical preparations
`
`base or in the acid addition salt, both of which are in­
`
`
`
`containing a compound of the present invention in the
`
`
`
`cluded within the scope of the invention. Thus, basic, form of dosage units for oral administration the com­
`
`as well as neutral or or mixed .salts may be obtained
`
`
`pound selected may be mixed with a solid, pulverulent
`
`
`
`
`carrier, such as lactose, saccharose, sorbitol, mannitol,
`
`
`hemi, mono, sesqui or polyhydrates. The acid addition
`may in a manner known per 10
`salts of the new compounds
`
`
`
`
`
`starch, amylopectin, cellulose derivatives or gelatin, as
`
`well as with an antifriction agent such as magnesium
`
`se be transformed into free base using basic agents such
`
`
`
`
`
`as alkali or by ion exchange. On the other hand, the free stearate, calcium stearate, and polyethyleneglycol
`
`bases obtained may form salts with organic or inorganic
`
`waxes. The mixture is then pressed into tablets. If
`
`
`
`coated tablets are desired, the above prepared core may
`
`
`acids. In the preparation of acid addition salts prefera­
`15
`
`
`be coated with a concentrated solution of sugar, which
`
`bly such acids are used which form suitable therapeuti-
`
`
`
`may contain gum arabic, gelatin, talc, titanium dioxide
`
`
`
`cally acceptable salts. Such acids include hydrohalogen
`
`
`or with a lacquer dissolved in volatile organic solvent
`
`acids, sulfonic, phosphoric, nitric, and perchloric acids;
`
`
`
`
`
`
`or mixture of solvents. To this coating various dyes may
`
`aliphatic, alicyclic, aromatic, heterocyclic carboxy or
`
`
`be added in order to distinguish among tablets with
`
`sulfonic acids, such as formic, acetic, propionic, suc­
`20
`
`
`
`different active compounds or with different amounts of
`
`
`cinic, glycolic, lactic, malic, tartaric, citric, ascorbic,
`the active compound present.
`
`
`maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic,
`
`
`
`Soft gelatin capsules may be prepared which capsules
`
`p-aminobenzoic, antranilic, p-hydroxybenzoic, salicylic
`
`
`contain a mixture of the active compound or com­
`
`or p-aminosalicylic acid, embonic, methanesulfonic,
`
`
`pounds of the invention and vegetable oil. Hard gelatin
`
`
`ethanesulfonic, hydroxyethanesulfonic, ethylenesul­
`naph-25
`
`
`
`capsules may contain granules of the active compound
`
`fonic, halogenbenzenesulfonic, toluenesulfonic,
`
`
`
`in combination with a solid, pulverulent carrier as lac-
`
`
`
`tylsulfonic or sulfanilic acids; methionine, tryptophane,
`
`
`
`
`tose, saccharose, sorbitol, mannitol, potato starch, corn
`lysine or arginine.
`
`These or other salts of the new compounds, as e.g.
`
`
`
`
`starch, amylopectin, cellulose derivatives or gelatin.
`
`Dosage units for rectal administration may be pre-
`
`
`picrates, may serve as purifying agents of the free bases
`30
`
`pared in the form of suppositories which contain the
`
`obtained. Salts of the bases may ·be formed, separated
`
`from solution, and then the free base can be recovered
`
`
`active substance in a mixture with a neutral fat base, or
`
`
`they may be prepared in the form of gelatin-rectal cap­
`from a new salt solution in a purer state. Because of the
`
`
`
`sules which contain the active substance in a mixture
`
`relationship between the new compounds in free base
`
`with a vegetable oil or paraffin oil.
`
`
`form and their salts, it will be understood that the corre­
`within the scope of the 35
`Liquid preparations for oral administration may be
`
`
`sponding salts are included
`invention.
`
`
`prepared in the form of syrups or suspensions, e.g. solu­
`
`tions containing from 0.2% to 20% by weight of the
`
`Some of the new compounds may, depending on the
`
`
`
`active ingredient and the remainder consisting of sugar
`
`
`
`choice of starting materials and process, be present as
`
`
`and a mixture of ethanol, water, glycerol and propylene
`
`
`optical isomers or racemate, or if they contain at least
`as an isomer 40
`
`
`
`glycol. If desired, such liquid preparations may contain
`
`two asymmetric carbon ato�s. be present
`
`
`
`
`
`colouring agents, flavouring agents, saccharin and car-
`
`mixture (racemate mixture).
`
`
`boxymethylcellulose as a thickening agent.
`
`
`The isomer mixtures (racemate mixtures) obtained
`
`
`
`
`Solutions for parenteral administration by injection
`
`
`may be separated into two stereoisomeric (diastereom­
`
`
`may be prepared as an aqueous solution of a watersolu­
`
`
`eric) pure racemates by means of chromatography or
`45
`
`
`ble pharmaceutically acceptable salt of the active com­
`
`fractional crystallization.
`
`
`pound, preferably in a concentration from 0.5% to 10%
`
`
`
`The racemates obtained can be separated according
`
`
`by weight. These solutions may also contain stabilizing
`
`to known methods, e.g. recrystallization from an opti­
`
`
`agents and/or buffering agents and may be manufac­
`
`
`cally active solvent, use of microorganisms, reactions
`
`tured in different dosage unit ampoules.
`
`with optically active acids forming salts which can be
`of 50
`· Pharmaceutical tablets for oral use are prepared in
`
`
`
`
`
`
`separated, separation based on different solubilities
`
`
`the following manner: The solid substances are ground
`
`
`
`the diastereomers. Suitable optically active acids are the
`
`
`
`or sieved to a certain particle size, and the binding agent
`
`L-and D-forms of tartaric acid, di-o-tolyl-tartaric acid,
`
`
`
`
`
`is homogenized and suspended in a suitable solvent. The
`
`malic. acid, mandelic acid, camphorsulfonic acid or
`
`
`therapeutically active compounds and auxiliary agents
`
`
`
`quinic acid. Preferably the more active part of the two
`55 are mixed with the binding
`
`antipodes is isolated.
`
`agent solution. The resulting
`
`
`mixture is moistened to form a uniform suspension hav­
`
`
`The starting materials are known or may, if they
`
`should be new, be obtained according to processes
`
`
`ing the consistency of wet snow. The moistening causes
`
`
`
`the particles to aggregate slightly, and the resulting
`known per se.
`
`mass is pressed through a stainless steel sieve having a
`
`
`In clinical use the compounds of the invention are
`in the form 60
`
`
`
`administered orally, rectally or by injection
`
`mesh size of approximately 1 mm. The layers of the
`
`
`
`of a pharmaceutical preparation which contains an ac­
`
`
`mixture are dried in carefully controlled drying cabinets
`tive component either as a free base or as a pharmaceuti­
`
`
`
`for approximately ten hours to obtain the desired parti­
`
`
`cle size and consistency. The granules of the dried mix­
`
`
`
`cally acceptable, non-toxic acid addition salt, such as
`
`
`
`
`hydrochloride, lactate, acetate, sulfamate, in combina­
`ture are sieved to remove any powder. To this mixture,
`The 65
`
`
`tion with a pharmaceutically acceptable carrier.
`
`
`
`disintegrating, antifriction and antiadhesive agents are
`
`
`carrier may be in the form of a solid, semisolid or liquid
`
`
`added. Finally, the mixture is pressed into tablets using
`
`or a capsule. These pharmaceutical prepara­
`
`diluent,
`
`a machine with the appropriate punches and dies to
`
`
`tions are a further object of the invention. Usually the
`
`
`
`
`obtain the desired tablet size. The pressure applied af-
`
`

`
`4,255,431
`
`8
`7
`fects the size of the tablet, its strength and its ability to
`
`
`
`were added and the mixture was refluxed for two hours.
`
`
`
`dissolve in water. The compression pressure used
`
`The sodium chloride formed was filtered off and the
`
`
`solution was evaporated in vacuo. The residue was
`
`should be in the range 0.5 to 5 tons. Tablets are manu­
`at the rate of 20.000 to 200.000 per hour. The 5
`
`
`dissolved in acetone and was treated with activ!'! car­
`factured
`
`
`
`tablets, especially those which are rough or bitter, may
`
`
`bon. An equivalent amount of concentrated hydrochlo­
`ric acid was added, whereupon the mono-hydrochlo­
`be coated with a layer of sugar or some other palatable
`
`ride of 2-[2-(3,5-dimethyl)pyridylmethylthio ]-4,6-(jime­
`
`
`
`substance. They are then packaged by machines having
`
`
`
`electronic counting devices. The different types of 10
`
`
`thyl)benzimidazole was isolated. Yield 0.05 moles.
`
`This compound was then oxidized in accordance
`
`
`
`packages consist of glass or plastic gallipots, boxes,
`
`with Example 1 above to give the corresponding sulfi­
`tubes and specific dosage adapted packages.
`melting point so· -ss· c.
`
`
`The typical daily dose of the active substance varies
`nyl compound,
`
`
`according to the individual needs and the manner of 15
`EXAMPLE 32 (METHOD B)
`
`
`administration. In general, oral dosages range from 100
`0.1 moles of 2-[Li-methylsulfinyl](S-acetyl-6-methyl)­
`to 400 mg/day of active substance
`and intravenous
`
`
`
`benzimidazole were dissolved in 150 mls of benzene. 0.1
`dosages range from 5 to 20 mg/day.
`
`moles 2-chloro-(3,5-dimethyl)pyridine were added and
`
`
`
`
`The following illustrates a preferred embodiment of 20
`the mixture was refluxed for two hours. The lithium­
`
`
`
`the invention without being limited thereto. Tempera­
`
`
`
`chloride formed was filtered off, and the solution was
`ture is given in degrees Centigrade.
`
`
`
`evaporated in vacuo. The residue was crystallized from
`
`
`
`The starting materials in the examples found below
`
`CH3CN, and recrystallized from the same solvent.
`
`
`
`meth-25 were prepared in accordance with the following
`Yield 0.82 moles of 2-(2-(3,5-dimethyl)pyridylmethyl­
`ods:
`
`sulfinyl]-(5-acetyl-6-methyl)benzimidazole melting at
`
`(I) a 1,2-diamino compound, such as a-phenylenedia­
`
`171° c.
`
`
`mine was reacted with potassium ethylxanthate (ac­
`cording to Or.;. Synth. Vol. 30, p. 56) to form a 2-mer-30
`EXAMPLE 33 (METHOD D)
`
`captobenzimtdazole; (2) the compound 2-chloromethyl­
`23.4 g of 2-[2-(3,4,5-trimethyl)pyridylmethylthio]
`
`
`
`pyridine was prepared by reacting 2-hydroxymethyl­
`formic acid and 16.6 g of o-(S"acetyl-6-methyl)­
`
`
`
`pyridine with thionylchloride (according to Arch.
`were boiled for 40 minutes in 100 ml
`phenylenediamine
`
`Pharm. Vol. 26; pp. 448-451 (1956)); (3) the compound
`was prepared by con-35 2-chloromethylbenzimidazole
`of 4 N HCI. The mixture was cooled and neutralized
`
`
`
`with ammonia. The neutral solution was then extracted
`
`
`densing a-phenylenediamine with chloroacetic acid.
`
`
`with ethyl acetate. The organic phase was treated with
`EXAMPLE 1
`
`
`active carbon and evaporated in vacuo. The residue was
`
`
`
`dissolved in acetone whereupon an equivalent of con­
`40
`28.9 g of 2-[2-(4,5-dimethyl)pyridylmethylthio]-(5-
`
`
`centrated HCI was added. The precipitated hydrochlo­
`
`
`acetyl-6-methyl)-benzimidazole were dissolved in 160
`
`ride was filtered off after cooling and the salt was re­
`ml of CHCl3, 24.4 g of m-chloroperbenzoic acid were
`
`
`
`crystallized from absolute ethanol and some ether.
`and cooling to s• C.
`
`added in portions while stirring
`acid 45
`Yield of 2-[2-(3,4,5-trimethylpyridyl)methylthio]-(5-
`
`
`After 10 minutes, the precipitated m-chlorobenzoic
`
`acetyl-6-methyl)benzimidazole was 6:5 g.
`
`
`
`was filtered off. The filtrate was diluted with CHzClz,
`
`This compound was then oxidized in accordance
`
`washed with NazC03 solution, dried over NazS04 and
`
`with Example 1 above, to give the corresponding sulfi­
`
`
`evaporated in vacuo. The residue crystallized when
`50
`
`nyl derivative. M.p. 190• C.
`
`diluted with CH3CN, and 2-[2-(4,5-di-methyl)pyridyl-
`
`methylsulfinyl]-(5-acetyl-6-methyl)benzimidazole was
`EXAMPLE 34 (METHOD C)
`from CH3CN. Yield 22.3 g; m.p. Iss• C.
`recrystallized
`22.0 g of 2-mercapto-(5-acetyl-6-methyl)ben­
`EXAMPLES 2-30
`
`zimidazole and 19.5 g of chloromethyl(4,5-dimethyl)�
`55
`
`
`
`pyridine hydrochloride were dissolved in 200 ml of
`
`The preparation of compounds of formula III la-
`
`
`95% ethanol. 8 g of sodium hydroxide in 20 ml of water
`
`
`belled 2-26 was carried out in accordance with Exam­
`
`
`were added, whereupon the solution was refluxed for
`ple 1 above. The compounds prepared are listed in
`
`two hours. The sodium chloride formed was filtered off
`for these com-60
`
`Table 1 which identifies the substituents
`in vacuo. The
`
`and the solution was e\faporated
`residue,
`pounds.
`
`
`2-[2-( 4,5-dimethyl)pyridylmethylthio ]-(5-acetyl-6-
`EXAMPLE 31 (METHOD C)
`
`
`methyl)benzimidazole, was recrystallized from 70%
`
`ethanol. Yield 10.6 g.
`0.1 moles of 4-6-dimethyl-2-mercaptobenzimidazole
`in 20 ml of water and 200 ml of ethanol 65 This compound was then oxidized were dissolved
`in accordance
`
`
`
`
`containing 0.2 moles of sodium hydroxide. 0.1 moles of with Example l above, to give the corresponding sulfi-
`M.p. tss• C.
`nyl derivative.
`
`2-chloromethyl-(3,5-dimethyl)pyridine hydrochloride
`
`

`
`9
`
`4,255,431
`
`10
`
`R4
`
`0 Rl
`
`,
`
`Rs
`
`. I
`
`"'
`
`··b">-t•
`•' 0
`16 N N R
`
`I
`H
`R2 R6 RJ R4
`Rl
`Ex.
`H CH3
`5-COCHJ
`6-CH3 H
`6-CH3 H H CH3
`5-COOCHJ
`H
`H
`H CH3
`5-COOCHJ
`6-CH3 H CH3 CH3
`5-COCHJ
`6-CH3 H CH3 CH3
`5-COOCHJ
`6-CH3 H CH3 H
`4-CHJ
`CH3 H
`6-CH3 H
`5-COCHJ
`CH3 CH3
`S-COCH3
`6-CH3 H
`6-CH3 H
`H OCH3
`5-COCHJ
`4-CHJ
`H OCH3
`6-CH3 H
`6-CH3 H CH3 OCH3
`5-COCHJ
`6-CH3 H CH3 H
`5-COOCHJ
`6-CH3 H CH3 CH3
`5-COOCHJ
`H OCH3
`6-CH3 H
`5-COOCHJ
`6-CH3 H
`H OC2Hs
`S-COOCH3
`6-CH3 H CH3 OCH3
`5-COOCHJ
`6-CH3 H CH3 OCH3
`5-COOCHJ
`H OCH3
`6-CH3 H
`S-COOCH3
`H CH3 H
`H
`S-COOCH3
`H CH3 OCHj
`H
`5-COOCHJ
`H CH3 OCH3
`H
`5-COCHJ
`H H OCH3
`H
`S-OCH3
`H CH3 OCH3
`S-OCH3
`H
`H CH3 OCH3
`H
`S-CH3
`H
`H CH3 OCH3
`H
`H CH3 OCH3
`5-C1
`H
`H H OC2H4QCH3
`S-CH3
`H
`H CH3 OCH3
`H
`5-COOC2Hs
`CH3 CH3 H
`H
`5-COOCHJ
`CH3 CH3 H
`5-CHJ
`H
`
`I
`2
`3
`4
`5
`6
`7
`8
`9
`10
`II
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`
`M.p.
`'C.
`Rs
`CH3
`158
`163
`CH3
`CH3
`141
`160
`H
`H
`163
`50-55
`CH3
`171
`CH3
`190
`CH3
`H
`165
`122
`H
`CH3
`156
`CH3
`144
`185
`CH3
`169
`H
`148
`H
`175
`H
`155
`CH3
`CH3
`158
`141
`CH3
`CH3
`142
`162
`CH3
`
`CH3 178
`156
`CH3
`CH3
`181
`165
`CH3
`CH3
`185
`119
`H
`150-5
`CH3
`CH3
`130
`CH3
`152
`
`tor and pH-meter (Radiometer, Copenhagen, Den­
`BIOLOGICAL EFFECT
`
`mark). Acid output was calculated as mmol H + /60
`40
`
`
`minutes. The percent inhibition compared to control
`
`
`
`The compounds of the invention possess worthwhile
`
`
`experiments was calculated for each compound and the
`
`
`
`
`therapeutic properties as gastric acid secretion inhibi­
`
`peak inhibitory effect is given in Table 2 below. The test
`
`tors as demonostrated by the following-tests. To deter­
`
`
`
`
`compounds, suspended in 0.5% Methocel ® (methyl
`
`
`mine the gastric acid secretion inhibitory properties,
`
`
`cellulose), were given intraduodenally in dgses from
`
`
`experiments have been performed on conscious dogs
`type and 45
`
`
`4-20 �-tmol/kg when the secretory response to pentagas­
`
`
`
`provided with gastric fistulas of conventional
`trin has reached a steady level.
`
`
`
`duodenal fistulas, the latter ones used for direct intradu­
`In the test prior known compounds were compared
`
`odenal administration of the test compounds. After 18
`
`
`
`
`with the compounds of the present invention as will be
`
`
`hours starvation and deprivation of water the dogs were
`
`evident from the Table 2 below.
`
`
`
`given a subcutaneous infusion of pentagastrin (1-4
`for 6-7 hours. Gastric juice was 50
`
`
`
`The following gastric acid inhibiting effect data were
`nmol/kg, h) lasting
`
`obtained for a number of compounds tested according
`
`
`
`collected in consecutive 30 minutes samples. An aliquot
`with 0.1 N NaOH to pH 7.0
`to the method described.
`of each sample was titrated
`
`for titrable acid concentration using an automatic titra-
`
`
`
`TABLE 2
`
`R6 RJ R4
`R2
`Ex. Rl
`H
`H CH3
`6-CH3
`I 5-COCHJ
`H CH3 CH3
`6-CH3
`4 S-COCH3
`H CH3 H
`6-CH3
`7 5-COCHJ
`H CH3 CH3
`6-CH3
`8 5-COCHJ
`H
`H OCH3
`6-CH3
`9 5-COCHJ
`
`Dose
`
`Effect
`
`Rs 1-'mol!kg % inhibition
`90
`CH3 2
`H
`60
`I
`CH3 2
`100
`CH3 4
`100
`H
`95
`2
`
`

`
`R4 ·:ex 0 •':(J •'
`N R ' • t ••
`Effect
`
`4,255,431
`
`11
`TABLE 2-continued
`
`Dose
`
`Rs /-lffiOl/kg % inhibition -
`
`N
`,_t_ CH ... I
`Rl I
`16 N
`�
`I H
`R2 R6 R3 R4
`
`Ex. Rl
`II 5-COCHJ 6-CH3 H CH3 OCH3
`CH3
`H
`5-COCHJ 6-CH3 H H CH3
`CH3
`H
`5-COCHJ 6-CH3 H H
`CH3
`2 5-COOCHJ 6-CH3 H H CH3
`H
`5 5-COOCHJ 6-CH3 H CH3 CH3
`CH3
`12 5-COOCHJ 6-CH3 H CH3 H
`CH3
`13 5-COOCHJ 6-CH3 H CH3 CH3
`H OCH3
`H
`14 5-COOCHJ 6·CH3 H
`15 5-COOCHJ 6-CH3 H H OC2Hs
`H
`H
`16 5-COOCHJ 6-CH3 H CH3 OCH3
`17 5-COOCHJ 6-CH3 H CH3 OCH3
`CH3
`CH3
`18 5-COOCHJ 6-CH3 H H OCH3
`H H
`CH3
`5-COOCHJ 6-CH3 H
`5-COOCHJ 6-CH3 H Br H
`H
`CH3
`6 4-CHJ 6-CH3 H CH3 H
`H
`10 4-CHJ 6-CH3 H H OCH3
`H
`4-CHJ 6-CH3 H H H
`H H
`CH3
`4-CHJ 6-CH3 H
`CH3
`H CH3
`H
`3 S-COOCH3 H
`CH3
`19 5-COOCHJ H
`H CH3 H
`CH3
`H CH3 OCH3
`20 5-COOCHJ H
`H H H
`CH3
`5-COOCHJ H
`H
`5-COOCHJ H
`H
`H H
`21 5-COCHJ H
`CH3
`H CH3 OCH3
`5-COCHJ H
`H H H
`C2Hs
`CH3
`22 5-0CHJ H
`H H OCH3
`23 5-0CHJ H
`CH3
`H CH3 OCH3
`H H CH3
`5-0CHJ H
`H
`CH3
`24 5-CHJ H
`H CH3 OCH3
`H
`H H
`CH3
`5-CHJ H
`H CH3 OCH3
`H
`25 H
`CH3
`H
`H
`H
`H H
`H
`is 5-COOC2Hs H
`H CH3 OCH3
`CH3
`H
`CH3
`H CH3 OCH3
`26 5-Cl
`27 5-CHJ H
`H OC2H40CH3 H
`H
`CH3 CH3 H
`29 5-COOCHJ H
`CH3
`
`
`•denotes a previously known compound
`
`0.5
`20
`8
`2
`2
`2
`4
`2
`4
`0.5
`0.5
`
`4
`4
`4
`2
`4
`12
`4
`2
`0.5
`20
`20
`0.5
`20
`
`0.5
`20
`0.5
`4
`0.5
`4
`0.5
`0.5
`0.5
`0.5
`
`70
`30
`80
`60
`90
`70
`80
`100
`75
`65
`90
`
`50
`0
`
`40
`40
`
`30
`50
`100
`
`60
`
`65
`90
`50
`60
`
`40
`
`65
`10
`50
`50
`60
`50
`50
`25
`30
`
`40
`
`-'
`
`12
`
`· . • f·
`
`EXAMPLE 36
`45
`
`2-[Z-(3,4-dimethyl)py�idyl��thylsulfinyl]-5-acetyl-6-
`EXAMPLE 35
`
`methyl)benzimidazole.,_ HCl (250 g) was mixed with
`
`
`lactose (175.8 g),.potato starch (199.7g) and colloidal
`
`A syrup containing 2% (weight per volume) of active
`
`
`silicic acid (32 g). The mixture w,as moistened with 10%
`
`
`
`substance was prepared from the following ingredients:
`50 solution
`
`
`of .gelatin and was.gro'uno through a 12-mesh
`
`
`sieve. After drying, p9tato_starch (160 g), talc (50 g) and
`
`
`magnesium stea�ate (5 g) were added and the mixture
`
`
`thus obtained was pressed into tablets (10.000), with
`2-[2-(4,5-dimethyl)pyridylmethylsulfinyl]­
`
`(5-acetyl-6-methyl)benzimidazole . HCI
`2.0 g
`
`
`each tablet containing 25 mg of active substance. Tab-
`Saccharin
`0,6 g
`55 lets can be prepared
`
`
`that contain any desired amount of
`Sugar
`30,0 g
`the active ingredient.
`Glycerin
`5.0 g
`
`Flavouring agent
`0.1 g
`EXAMPLE 37
`Ethanol96%
`10.0 ml
`Granules were prepared from 2-[2-(3,5-dimethyl)­
`to obtain a final volume of 60
`Distilled water (sufficient
`
`pyridylmethylsulfinyl]-(5-acetyl-6-methyl)ben­
`
`
`100 ml) Sugar, saccharin and the acid addition salt were
`
`
`zimidazole-p-hydroxybenzoate (250 g), lactose (175.9 g)
`dissolved in 60 g of warm water. After cooling, glycerin
`
`
`
`
`and an alcoholic solution of polyvinylpyrrolidone (25
`
`
`
`and a solution of flavouring agents dissolved in ethanol
`
`
`g). After drying, the granules were mixed with talc (25
`were added. Water was added to the mixture to obtain
`
`
`g), potato starch (40 g), and magnesium stearate (2.50 g)
`65 and were pn::ssed into 10.000 tablets.
`a final volume of 100 mi.
`
`These tablets are
`
`The above given active substance may be replaced
`
`
`
`first coated with a 10% alcoholic solution of shellac and
`
`
`with other pharmaceutically acceptable acid addition
`
`
`
`thereupon with an aqueous solution containing saccha­
`salts.
`
`rose (45%), gum arabic (5%), gelatin (4%), and dyestuff
`
`

`
`4,255,431
`
`14
`13
`2-[2-(4-ethoxy)-pyridylmethylsulfinyl]-(5-carbome­
`(0.2%). Talc and powdered sugar were used for pow­
`thoxy-6-methyl)-benzimidazole,
`
`
`dering after the first five coatings. The coating was then
`2-[2-(3-methyl-4-methoxy)-pyridylmethylsulfinyl]-(5-
`
`covered with a 66% sugar syrup and polished with a
`carbomethoxy-6-methyl)-benzimidazole,
`
`
`solution of 10% carnauba wax in carbon tetrachloride.
`5
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`EXAMPLE 38
`finyl]-(5-carbomethoxy-6-methyl)-benzimidazole,
`2-[2-(4-methoxy-5-methyl)-pyridylmethylsulfinyl]-(5-
`2-[2-(3,5-dimethyl)pyridylmethylsulfinyl)-(5-acetyl-
`carbomethyoxy-6-methyl)-benzimidazole,
`
`
`6-methyl)benzimidazole hydrochloride ( l g), sodium
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`
`
`chloride (0.6 g) and ascorbic acid (0.1 g) were dissolved
`in sufficient amount of distilled water to give 100 ml of 10
`
`
`finyl]-5-carbomethoxy )-benzimidazole,
`
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`
`
`
`solution. This solution, which contains 10 mg of active
`finyl]-(5-acetyl)-benzimidazole,
`
`substance for each ml, was used in filling ampoules,
`2-[2-(4-methoxy-5-methyl)-pyridylmethylsulfinyl]-(5-
`
`
`which were steralized by heating at 120" C. for 20 min­
`methoxy )-benzimidazole,
`utes.
`15
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`We claim:
`finyl]-(5-methoxy)-benzimidazole,
`
`
`
`1. A method of inhibiting gastric acid secretion by
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`
`
`administering to mammals, including man, suffering
`finyl]-(5-methyl)-benzimidazole,
`
`
`
`from gastric acid secretion disturbances a compound of
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`the formula III
`20
`finyl]-benzimidazole,
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul­
`(III)
`
`finyl]-(5-chloro)-benzimidazole or a pharmaceuti­
`
`cally acceptable salt thereo